Lipid Guideline Controversies in 2014: The Decision is Yours

Carl E. Orringer, MD, FACC, FNLA

Objectives

• To provide an overview of the American College of Cardiology/American Heart Association and the National Lipid Association lipid management approaches for ASCVD prevention

• To identify the similarities and differences between the two approaches

• To provide the information needed to decide which approach to use and when

Two ASCVD Prevention ApproachesTwo Different Perspectives

External reviewer Author

US age-standardized death rates attributable to CVD, 2000 to 2010

Go A S et al. Circulation. 2014;129:e28-e292

Copyright © American Heart Association, Inc. All rights reserved.

Release of NCEPATP III Release of NCEP

ATP III Update

Mean age-adjusted LDL-C trends 2001–2011 in the United States: Analysis of 105 million patient recordsfrom a single national diagnostic laboratory

10.1371/journal.pone.0063416

Is There a Need for a Dramatic Change in Approach to ASCVD Prevention?

CCSIASEAS/ESCJASNICENLA

Changes in:Evidence baseCentral focusLipid goalsUse of non-statinsRisk calculator

ACC/AHA

The Rules

• The topic will be identified • Common ground and differences will

be noted• Appropriate supporting evidence will

be introduced• Summary will be provided• You make the decision

Evidence Base

ACC/AHA• Randomized controlled

trials (RCT) of statin therapy

• Meta-analyses of RCT

NLA• RCT of statins and non-

statin drug therapy• Meta-analyses of RCT• Observational

epidemiologic studies• Genetic studies• Metabolic studies• Mechanistic studies

Randomized Controlled Trials (RCT)• Systematically test effect(s) of an intervention on pre-

specified outcomes in defined populations• Their use minimizes confounding • Study populations are often not diverse and exclusion

criteria may hamper physician’s ability to apply results to real-world patients

• Most are designed to gain regulatory registration for pharmaceutical agents; lifestyle trials, studies of generic drugs or of those produced by smaller companies may be under-represented in RCT due to inadequate financial support

Observational Epidemiologic Studies

• Worldwide in scope and may assess ASCVD risk across populations

• Cohort studies evaluate mortality and morbidity within populations

• Confounding may occur even after matching, stratification, and multivariate adjustment because of measurement error or unmeasured or unknown risk factors

Observational Epidemiologic Cohort Study of 2146 Patients with FH and no CHD at Baseline

Versmissen J, et al BMJ 2008; 337: a2423

Genetic Studies

• Genetic epidemiology reduces the likelihood of confounding by focusing on single variables: genetic mutations

• Identification of specific mutations may serve to generate hypotheses for other types of trials

• Often limited in patient selection and costly

Data Demonstrating Genetic Variants Affecting ASCVD Risk

• Sequence variants in the gene encoding for PCSK9 resulting in loss of function mutations are associated with 28% reduction in LDL-C, an 88% reduction in CHD risk and provide support for the value of long term low LDL-C in promoting CHD risk reduction

J Cohen et al. N Engl J Med 2006;354:1264-72

Evidence Base: Summary• ACC/AHA

– By limiting the scope to RCT of statins and meta-analyses of RCT, only the highest level of evidence on statins in defined populations is employed to assess ASCVD outcomes

• NLA– By including evidence from RCT and other sources, a

broader evidence base for clinical decision making is employed . This approach is consistent with the perspective of previous NCEP ATP’s and the international community

Central Focus of GuidelineACC/AHA

• Identification of statin benefit groups

• Initiation and maintenance of high or moderate intensity statin therapy

• Abandonment of lipid goals• Avoidance of non-statin

therapy because of “unfavorable risk/benefit ratio.”

NLA• Identification of an individual

patient’s ASCVD risk based on clinical parameters and risk factors

• Initiation of ASCVD risk-based lipid-lowering therapy

• Maintenance of lipid goals to assess effective reduction of atherogenic lipoproteins and enhace adherence

• Use of high or moderate dose statins, ±non-statins, if necessary, to achieve goals

ACC/AHA Statin Benefit Groups

• Individuals with clinical ASCVD without New York Heart Association class II-IV heart failure or receiving hemodialysis (H preferred; M if age >75 or if not candidate for H).

• Individuals with primary elevations of LDL-C ≥190 mg/dl (H preferred; M if not candidate for H).

• Individuals age 40-75 years with diabetes, and LDL-C 70-189 mg/dl without clinical ASCVD (M if 10 yr risk <7.5%; H if ≥7.5%).

• Individuals without clinical ASCVD or diabetes, who are age 40-75 years with LDL-C 70-189 mg/dl, and have an estimated 10-year ASCVD risk of ≥ 7.5% using Pooled Cohort Equations (M or H).

H=High intensity statin; M=Moderate intensity statin

High- and Moderate-Intensity Daily Statin Therapy

• High Intensity (Lowers LDL-C ≥ 50%)– Atorvastatin 40-80 mg– Rosuvastatin 20-40 mg

• Moderate Intensity (Lowers LDL-C 30-50%)– Atorvastatin 10 (20) mg– Rosuvastatin (5) 10 mg– Simvastatin 20–40 mg– Simvastatin 80 mg*– Pravastatin 40 (80) mg– Lovastatin 40 mg– Fluvastatin XL 80 mg– Fluvastatin 40 mg 2x/day– Pitavastatin 2–4 mg

Bold = Tested in RCT andreviewed by Expert PanelYellow= Not tested in RCT reviewed by Expert Panel

Efficacy of Intensive Lowering of LDL-C in Subjects with Low Baseline LDL-C

• Meta-analysis of RCT’s of >1000 participants and ≥2 years treatment duration of more versus less intense statin trials involving 169,138 subjects

• The major vascular event reduction, among in those with baseline LDL-C <77mg/dL per further 39 mg/dL reduction was 29% (99% CI 2-48, p=0.007); in those with baseline LDL-C <70 mg/dl, similar reduction in LDL-C continued to demonstrate MVE reduction (RR 0.63, 99% CI 0.41-0.95, p=0.004).

Cholesterol Treatment Trialists Collaboration. Lancet 2010;376:1670-81

ACC/AHA Perspective on Statin Therapy

• Statin intensity trials showed clear benefit for high intensity versus moderate intensity statins

• Because fixed doses, not dosage titrations, were employed, one should not assume that a dosage titration strategy is correct or that addition of non-statins to achieve low LDL-C is indicated

ACC/AHA Perspective on Non-StatinLipid Drug Therapy

• Non-statin drugs without demonstrated ASCVD risk reduction may favorably alter lipids but have an unfavorable risk/benefit ratio– Niacin in AIM-HIGH and HPS-2 THRIVE– Fibrates in ACCORD-Lipid, FIELD– Lack of ASCVD event end-point data on ezetimibe– CETP inhibitors torcetrapib and dalcetrapib

• The use of non-statin drugs should generally be avoided

Overview of the NLA Recommendations

1. All preventive therapy begins with risk assessment and a provider-patient discussion of the pros and cons of therapy

2. Lifestyle therapy is at the basis of all ASCVD preventive recommendations, regardless of baseline risk

3. Judicious use of evidence-based drug therapy, particularly moderate and high-dose statins, is associated with optimal ASCVD risk reduction

4. When excessive circulating atherogenic cholesterol (non-HDL-cholesterol and LDL cholesterol) persists after appropriate lifestyle and statin therapy, the use of non-statin therapy may be considered

5. Long-term follow-up fostered by provider-patient communication is essential for optimal ASCVD prevention

NLA ASCVD Risk Category CriteriaRisk Category Criteria

Very High • ASCVD• Diabetes mellitus (type 1 or 2) ≥2 other major ASCVD risk factors; or Evidence of end-organ damage

High • ≥3 major ASCVD risk factors• Diabetes mellitus (type 1 or 2) 0-1 other major ASCVD risk factor, and no evidence of end-organ damage• Chronic kidney disease Stage 3B or 4• LDL-C ≥190 or non-HDL-C ≥220 mg/dL

Moderate • 2 major ASCVD risk factors• For specific clinical features, high

quantitative risk score or specific biomarker levels, consider reclassification to high risk

Low • 0-1 major ASCVD risk factor• For specific clinical features, consider

reclassification to moderate risk

NLA ASCVD Risk Categories, Levels for Consideration of Drug Therapy and Treatment Goals

Risk Category Consider Drug Therapy Treatment Goal

Non-HDL-C /LDL-C Goal (mg/dL)

Non-HDL-C/LDL-C Goal (mg/dL)

Very-high ≥100≥70

<100<70

High ≥130≥100

<130<100

Moderate ≥160≥130

<130<100

Low ≥190≥160

<130<100

For patients with ASCVD or diabetes mellitus, consider use of moderate or high intensity statins, irrespective of baseline atherogenic cholesterol levels.

NLA Perspective on Statin Therapy• Statin therapy is the most potent and evidence-

based approach to lowering atherogenic lipoproteins (non-HDL-C and LDL-C)

• Statin intensity trials showed clear benefit for high-intensity versus moderate-intensity statins

• Broad-based evidence supports “lower is better” concept, and provides an opportunity for clinicians to address residual risk above that addressed by appropriately-dosed statin therapy

NLA Perspective onNon-Statin Lipid Drug Therapy

• If non-HDL-C and LDL-C goals are not achieved with maximal tolerated statin therapy, the addition of non-statin therapy should be considered to lower atherogenic cholesterol levels and to achieve goals – Doctors can be instructed not to use niacin in patients on

aggressive statin regimens– As ezetimibe is safe and lowers atherogenic cholesterol, its use

may be considered in selected patients with elevated non-HDL-C and/or LDL-C

– Resins may be considered in selected patients– Meta-analyses of fibrate therapy in subgroups with atherogenic

dyslipidemia suggest ASCVD risk reduction

Is High-Dose Statin Therapy the End of the Line?

Meta analysis of 8 statin RCT involving 38, 153 subjects of whom 5,387 had 6,286 major CV events and had baseline and 1 year lipids and lipoproteins

Variability of Achieved LDL-C With High-Intensity Statin Therapy

Boekholdt SM et al. J Am Coll Cardiol 2014;64: 485-94

From TNT,SPARCL, IDEAL andJUPITERdemonstrating variability of LDL-C lowering.>40% did not achieveLDL-C <70 mg/dl on atorvastatin 80 or rosuvastatin 20 mgdaily

Waterfall plot of Individual values

Very Low LDL-C and Non-HDL-C in Statin Trials and Major CVD Event Risk

<50, <75 50-74, 75-99 75-99, 100-124 100-124, 125-149 125-149, 150-174 150-174, 175-199 >=175, >=200

0.44

0.510.56 0.58

0.64

0.71

1.00

0.570.60

0.640.69

0.75

0.89

1.00

LDL-C Non-HDL-C

Boekholdt et al. JACC 2014;64:485-494

On Treatment LDL- C, Non-HDL-C mg/dL

Central Focus of Guidelines:Summary

• ACC/AHA: define statin benefit groups; risk/benefit discussion; use moderate or high-intensity statin therapy with lifestyle change as background therapy; generally avoid non-statin drug therapy; no lipid goals

• NLA: identify ASCVD risk level; risk/benefit discussion; emphasize healthy lifestyle and use moderate or high-intensity statin therapy, and if necessary, adjunctive non-statin therapy, to lower atherogenic cholesterol; maintain lipid goals (non-HDL-C is favored lipoprotein target)

Risk Calculators

ACC/AHA• Use Pooled Cohort Risk

calculator in non-Hispanic Whites and non-Hispanic African Americans age 40-79 without ASCVD and not on statin therapy; may be considered in other populations

• Assessment of lifetime risk may be considered in those aged 20-59 with no ASCVD and not at high short-term risk

NLA• Consider 10-year FRS,

ACC/AHA Pooled Cohort Risk calculator, or 30-year risk in those with 2 major ASCVD risk factors; re-classify to higher risk those with ≥10% 10-year FRS, ≥15% ACC/AHA risk, or ≥45% long-term risk

http://www.tools.cardiosource.org/ascvd-risk-estimator

Key Disclaimer of the ACC/AHA Pooled Cohort Risk Calculator

• It does not definitively recommend statin therapy for individuals with 10-year risk ≥7.5%

• It advises that for such individuals before initiating statin therapy “it is reasonable for clinicians and patients to engage in a discussion which considers the potential for ASCVD risk reduction benefits and for adverse effects, for drug-drug interactions and patient preferences for treatment.”

Pooled Cohort Equations: Criticism

• Early criticism of the Pooled Risk calculator centered around lack of long-term prospective validation and possible overestimation of risk

• When the Pooled Risk Equation calculator was applied to 3 large, more recent primary prevention cohorts, the Women’s Health Study, the Physician’s Health Study and the Women’s Health Initiative Observational Study, it systematically overestimated observed risk by 75-150%, roughly doubling the actual observed risk

Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease.Lancet 2013 10.1016/S0140-6736(13)62388-0. published Nov 20. PubMed

Pooled Cohort Equations: Defense

• Validation was more extensive than any other previous risk equations

• The primary prevention cohorts of WHS, PHS and WHI were likely significantly healthier than the general population

• In WHS and PHS some risk factors were self-reported in ranges rather than directly measured, resulting in imprecision

• All 3 cohorts might have been subject to some downstream initiation of statins

Lloyd-Jones DM, Goff D and Stone N. The Lancet, Early Online Publication, 4 December 2013 doi:10.1016/S0140-6736(13)62348-X

Pooled Cohort Equations: Criticism • An analysis of the Women’s Health Study

examined data from 632 women who had an ASCVD event over a median follow-up of 10 years

• After adjustment for the intervention effects of statins, revascularization and hypothetical confounding by indication the ratios of predicted to observed events were 1.8 in those with 0-<5% and 5-7.4% estimated 10-year risk and 1.3 in the groups with 7.5-10% and >10% estimated 10 year risk groups Cook NR, Ridker PM. JAMA Intern Med Published Online October 6, 2014

Pooled Cohort Equations: Defense• 10,997 adults, ages 45-79, in the Reasons for Geographic

Distribution and Racial Differences in Stroke study, without ASCVD or diabetes, with total cholesterol 70-189 mg/dl and not taking statins were examined for incident ASCVD at 5 years, and additional analysis in 3,333 Medicare beneficiaries added additional ASCVD events as defined in Medicare Claims data.

• There was a high degree of correlation between observed and predicted ASCVD incidence per 1,000 person-years in groups with <5%, 5-<7.5%, 7.5-<10% and ≥10% (calibration) and moderate to good ability to accurately rank-order individuals (discrimination) (C-statistic ~0.7).

Muntner P et al. JAMA 2014;311:1406-1415

Pooled Cohort Equations: Criticism• Application to elderly populations

– When the risk calculator was applied to 4,854 Rotterdam Heart Study participants with a mean age of 65 years, 96.4% of men and 65.8% of women would be recommended statins• The average predicted versus observed

cumulative incidence of hard ASCVD events was 21.5 vs. 12.7 % for men and 11.6 vs. 7.9% for women (poor calibration)

Kavousi M et al. JAMA 2014: 311(14): 1416-23

ACC/AHA Risk Calculator: Possible Overtreatment in Older Patients?

Age Total cholesterol

HDL cholesterol

Systolic BP Treatment for HBP

Diabetes Smoker 10-year ASCVD risk

60 AA♂ 170 50 125 No No No 7.5%

65 AA♀ 178 50 130 No No No 7.5%

60 C ♂ 170 47 125 No No No 7.5%

NLA Perspective on Risk Calculators

• Although any of 3 risk calculators are suggested for consideration (10 year Framingham risk, lifetime Framingham risk, ACC/AHA Pooled Cohort Risk Calculator), risk calculators measure diverse endpoints and have limited application in various ethnic and age groups

• The interpretation of a particular risk level using any risk calculator in a given patient must be done using careful clinical judgment

Risk CalculatorsACC/AHA

• Use Pooled Cohort Risk calculator in non-Hispanic whites and non-Hispanic African Americans age 40-79 without ASCVD and not on statin therapy; may be considered in other populations

• Assessment of lifetime risk may be considered in those aged 20-59 with no ASCVD and not at high short-term risk

NLA• Consider 10-year FRS,

ACC/AHA Pooled Cohort Risk calculator, or 30-year risk in those with 2 major ASCVD risk factors; re-classify to higher risk those with ≥10% 10-year FRS, ≥15% ACC/AHA risk, or ≥45%% long-term risk

Lipid Guideline Controversies: Common Threads Between ACC/AHA and NLA

• Lifestyle therapy is warranted for ASCVD risk reduction, whether or not drug therapy is used

• Patients with ASCVD, FH and diabetes are candidates for moderate or high-dose statins

• Risk calculators aid in, but do not take the place of clinical judgment

• Whether or not lipid goals are set, regular lipid follow-up is warranted to assess adherence

• Patient engagement in preventive care decision making aids in long-term adherence

What’s Ahead in Guidelines?

• A new app for the NLA Recommendations Part 1• New ACC/AHA performance measures related to

the 2013 Blood Cholesterol Guideline and another app related to the Guideline

• NLA Recommendations Part 2 on special populations (women, elderly, HIV, south Asian Indians, Hispanic, CKD, heart failure, rheumatoid arthritis)

• A new NLA Self-Assessment Program on Guidelines

The Decision is Yours

ACC/AHA NLA